Method of treating spinal disk

ABSTRACT

A method of treating a spinal disk according to the present invention can include inserting an alloplastic bulking agent into the spinal disk to treat the defect. The alloplastic bulking agent has a plurality of microparticles and a suspending agent comprising hyaluronic acid. The bulking agent results in at least one of sealing the defect, increasing a pressure of the disk, increasing a height of the disk, improving stability of the disk and improving structural integrity of the disk.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of PCT Application No.PCT/US2016/013718, filed Jan. 15, 2016, which claims priority to U.S.Provisional Patent Application Ser. No. 62/104,632, filed on Jan. 16,2105 and entitled “Method of Treating Spinal Internal Derangement.” Eachof the above applications is hereby incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates generally to surgical implants and, moreparticularly, relates to alloplastic spinal disk implants andprocedures.

Description of the Related Art

Spinal disks comprise a central region called the nucleus pulposussurrounded by a second region known as the annulus fibrosis. The annulusfibrosis portion comprises collagen fibers that may weaken, rupture, ortear, leading to compromised annular confinement of the nucleus andproducing disk bulges, herniations and other disk pathologies. The majorcauses of persistent, often disabling, back pain are disruption of thespinal disk annulus fibrosis, chronic inflammation of the spinal disk(e.g., herniation), or relative instability of the vertebral bodiessurrounding a given spinal disk, such as the instability that oftenoccurs due to a degenerative disease. In some cases, the spinal disktissue is irreparably damaged, thereby necessitating surgical removal ofa portion of the spinal disk or the entire spinal disk to eliminate thesource of inflammation and pressure. Following removal, spinal disks maycontain annular defects or openings that can increase the possibility ofrecurrent complications such as, for example, future nuclearherniations.

Some methods to treat such defects focus on injecting compositionscontaining collagen based suspending agents into an affected spinaldisk. For example, U.S. Pat. No. 8,398,638 discloses a compositionincluding microparticles suspended in a collagen suspending agent, andteaches that such a composition can be utilized to treat a damagedspinal disk. Similarly, U.S. Pat. No. 8,586,089 describes a compositionof microparticles and a biocompatible carrier medium in the form ofcross-linked collagen and biocompatible gelatin for treating a patient'stissue or fluids. It is directed to adjusting the ratio of cross-linkedcollagen in the biocompatible carrier medium in order to improve theviscosity of the composition. More specifically, U.S. Pat. No. 8,586,089is directed towards using cross-linked collagen in a biocompatiblecarrier medium in order to improve “resistance to deformation,” “shearmodulus,” and “dynamic viscosity,” as well as to allow injection withoutexcessive force.

SUMMARY OF THE INVENTION

In accordance with one aspect of the present invention, methods areprovided for treating and sealing invertebrate spinal disks that havetears or fissures on the annulus fibrosus.

In one embodiment, a method of treating a spinal disk comprisesdelivering an agent to the spinal disk, wherein the agent comprises aplurality of microparticles and hyaluronic acid.

In another embodiment, a medical kit comprises an agent comprisingmicroparticles and hyaluronic acid and one or more surgical toolsconfigured for repairing at least one spinal disk.

In another embodiment, an implant agent comprises a plurality ofmicroparticles and hyaluronic acid, for use in repairing and/orimproving structural integrity of spinal disks.

In addition, a method of treating a spinal disk comprises placing aplurality of particles into an interior portion of the spinal disk.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a test article within a nucleus polposus ofintervertebral disc sections L1-L2 of a test animal 13Y.

FIG. 2 depicts a cleft in a nucleus pulposus of intervertebral discsections L4-L5 of a test animal 13R.

DETAILED DESCRIPTION OF THE INVENTION

Any feature or combination of features described herein are includedwithin the scope of the present invention provided that the featuresincluded in any such combination are not mutually inconsistent as willbe apparent from the context, this description, and the knowledge of oneskilled in the art. In addition, any feature or combination of featuresmay be specifically excluded from any embodiment of the presentinvention. For purposes of summarizing the present invention, certainaspects, advantages and novel features of the present invention aredescribed herein. Of course, it is to be understood that not necessarilyall such aspects, advantages or features will be embodied in anyparticular embodiment of the present invention.

In reference to the disclosure herein, for purposes of convenience andclarity only, directional terms, such as, top, bottom, left, right, up,down, upper, lower, over, above, below, beneath, rear, and front, may beused. Such directional terms should not be construed to limit the scopeof the invention in any manner. It is to be understood that embodimentspresented herein are by way of example and not by way of limitation. Theintent of the following detailed description, although discussingexemplary embodiments, is to be construed to cover all modifications,alternatives, and equivalents of the embodiments as may fall within thespirit and scope of the invention.

The present invention provides compositions and methods for selectivelytreating defects within or on a spinal disk. These procedures includelaminectomy/diskectomy procedures for treating herniated spinal disks,decompressive laminectomy for stenosis in the lumbosacral and cervicalspine, medial facetectomy, posterior lumbosacral and cervical spinefusions, treatment of scoliosis associated with vertebral disease,foraminotomies to remove the roof of the intervertebral foramina torelieve nerve root compression and anterior cervical and lumbardiscectomies. These procedures may be performed through open procedures(e.g., laminotomy, laminectomy, hemilaminotomy and hemilaminectomy), orusing minimally invasive techniques, such as thoracoscopy, arthroscopy,laparascopy, diskogrophy (e.g., performed percutaneously through aposterior, posterolateral, lateral, anterior or anterolateral approachto the spinal disk) or the like.

In accordance with an aspect of the present invention, a biocompatiblealloplastic implant is provided for sealing tears or other defects orconditions of a spinal disk, such as a rent in the annulus fibrosis of aspinal disk. The biocompatible alloplastic implant can be inserted intoa ruptured spinal disk, filling a portion of the nucleus pulposus and/orannulus fibrosis and providing a seal. In one implementation, thebiocompatible alloplastic implant is inserted into a center region ofthe ruptured spinal disk. According to certain aspects, thebiocompatible alloplastic implant is inserted into the nucleus pulposusafter a microdiscectomy which closes the iatrogenic rent or annulotomythat the surgeon creates thereby minimizing the risk for recurrentherniation, or is administered as an injectable sealant into the centerof the spinal disk, for example, after a diskography procedure in orderto seal one or more annular tears.

To the extent such tears or defects are treated using the presentinvention, risks for recurrent spinal disk herniations and possiblerevision surgeries can be attenuated or eliminated. Such revisionstypically entail slightly larger incisions, greater bony resection,removal of scar tissue, more difficult retraction, increased bleeding,increased anesthetic time, and increased risk for battered nerve rootsor possible injury to the dura or root sleeves resulting in potentialCerebro-Spinal Fluid (CSF) leak, fistula, infection, etc. As a result ofthe minimized need for revision surgery, surgical outcome can beimproved and the need for repeat surgery at the same level can bedecreased.

Moreover, with the perhaps increased use of provocative diskography toascertain, for example, whether adjacent segments above or below aplanned fusion need to be incorporated, a user can instill thebiocompatible alloplastic implant to minimize the extension of thefusion to the adjacent segment. Using conventional procedures, forexample, if an unstable motion segment were planned to be fused andpreoperative provocative diskography revealed the adjacent segment(e.g., the adjacent spinal disk) as also being symptomatic, that levelwould be included in the fusion mass. However, in accordance with anaspect of the present invention, the biocompatible alloplastic implantof the present invention can be instilled into the adjacent segmentprior to the surgery to help seal the annular tear or tears. In oneimplementation, the biocompatible alloplastic implant of the presentinvention can be instilled into the adjacent segment during thepreoperative provocative diskography. As a result, the use of thepresent biocompatible alloplastic implant is not limited tomicrodiscectomy or open diskectomy procedures, but can also be used forclosed procedures in which, for example, imaging studies have proventhat there are annular tears or rents which reproduce concordant pain.Installation of the biocompatible alloplastic implant, in accordancewith one implementation of the present invention, may be especiallysuited for annular tears which are not asymptomatic and which do notproduce discordant pain.

Implantation of the biocompatible alloplastic implant, if performed inthe context of a closed procedure, can be accomplished from a posteriormidline or posterolateral approach or a direct lateral approach. Ifperformed in the context of an open procedure, implantation of thebiocompatible alloplastic implant can be achieved from a posteriormidline approach, posterolateral approach, anterior, anterolateral, ordirect lateral approach. It is therefore possible that if an anteriorapproach is being utilized for an anterior diskectomy alone, thebiocompatible alloplastic implant of the present invention can beinstilled through a syringe and needle into that nucleus pulposus spaceafter, for example, an offending spinal disk fragment or fragments havebeen removed. In certain implementations, the material can be introducedvia flexible catheters of variable length and diameter, such as, forexample, standard percutaneous needles and standard catheter tips knownin the industry. In an exemplary open procedure where for example alaminectomy or microdiscectomy is being performed, it may be easier toinject the biocompatible alloplastic implant as used according to thepresent invention with the aid of an injection syringe, such as ansyringe with a 3 or 4″ 18-gauge needle. In representative embodiments,the size of the needle can range from 14-gauge to 26-gauge, from18-gauge to 25-gauge, or from 20-gauge to 24-gauge, or 22 to 26 gauge.In certain implementations the size of the needle may be 20 gauge orsmaller, 21 gauge or smaller, or 22-gauge or smaller. These gaugeclassifications correspond to industry standard inner and outerdiameters, with an 18 gauge needle having an outer diameter of less than1300 microns (nominally 1270 microns) and an inner diameter of less than900 microns (nominally 838 microns). Needles in the 22 to 26 gauge rangecorrespond to outer diameters of between 750 and 450 microns, and innerdiameters between 450 and 240 microns. In some embodiments, theinjection syringe may include a needle having a length of at least 3inches, at least 5 inches, at least 6 inches, or at least 8 inches. Insome embodiments, the needle comprises a pencil point needle. A pencilpoint needle can create a smaller perforation in the annulus fibrosis,which can limit extrusion of the biocompatible alloplastic implantthrough the perforation. Smaller perforations may also improve patientcomfort. Larger perforations in the dura, such as those created with an18-guage needle, can lead to head and neck pain in a patient, such as aheadache. A needle causing a smaller perforation, such as a 25-gaugeneedle, may decrease the risk of such pain.

The maturation of the biocompatible alloplastic implant of the presentinvention, in accordance with an aspect of the present invention, canover time afford additional, or at least partial, stabilization to theannulus fibrosis which can then provide additional support to the motionsegment involved. This change in the biomechanics can translate into apartial increase in the stability for this motion segment. Having anannular tear generally can cause a weakening in the supporting structureof the motion segment. Treating the nucleus pulposus of a spinal diskwith the biocompatible alloplastic implant of the present invention canin certain implementations allow a maximum amount of the nuclearmaterial to remain centrally located and/or can increase the integrityof the surrounding annular fibers.

The biocompatible alloplastic implant of the present inventionpreferably comprises a plurality of microparticles and a suspendingagent. The suspending agent preferably comprises hyaluronic acid.Hyaluronic acid is a naturally occurring biodegradable polymer. It canbe found in the extracellular matrix of all animal tissue, and isinvolved in several biological functions. Hyaluronic acid providesmechanical features to body tissue. It also has a role in regulatingcell adhesion and cell motility. Furthermore, hyaluronic acid isinvolved in manipulating cell differentiation and proliferation. In someembodiments, the hyaluronic acid is in powder form prior tosolubilization. In other embodiments, the hyaluronic acid may be infiber form or cake form prior to solubilization. The suspending agentcan further comprise at least one of water and saline. Furthermore, thesuspending agent can be admixed with a tenside, such as Tween ad, sincesuch a tenside changes the surface tension of water so that themicroparticles have a more uniform distribution. The suspending agentmay also include sterile Phosphate Buffered Solution (PBS). In certainimplementations, the concentration of hyaluronic acid in PBS is at most1.8%. The concentration of hyaluronic acid in PBS can be between 1.0%and 3.0% or 1.6% and 2.4%, In certain implementations, the concentrationof hyaluronic acid in PBS may be 1.2%.

While previous attempts to treat damaged spinal disks have focused oncollagen based suspending agents, a biocompatible alloplastic implantincluding a suspending agent with hyaluronic acid has many advantagesover a suspending agent utilizing collagen. Hyaluronic acid is highlyhydrophilic, which allows it to occupy a large volume relative to mass.The hydrophilic nature of hyaluronic acid further allows for the bindingof water molecules to a suspending agent with hyaluronic acid in orderto increase the viscosity of the biocompatible alloplastic implant. Thesuspending agent comprising hyaluronic acid can bind water molecules,thus increasing viscosity, after insertion into the interior of a spinaldisk. Generally, a higher viscosity composition will require a largerneedle and greater force, so increasing viscosity after injection allowsfor a wider range of needles to be used for injection. Furthermore,increasing viscosity after injection can prevent extrusion through theperforation created by the needle in the spinal disc. Hyaluronic acid isalso capable of forming gels at low concentrations and can withstandcompressive forces when water is drawn into the hyaluronic acid matrix.Hyaluronic acid also demonstrates no tissue or species specificity,which allows for minimal immune response or rejection such as that whichcan occur when using traditional suspending agents comprising collagen.

Previous attempts to improve treatment with collagen based implants havefocused on improving the viscosity of a suspending agent by altering theratio of cross-linked collagen in the suspending agent. In comparison toa collagen based suspending agent, the viscosity of a suspending agentcomprising hyaluronic acid is more favorable for injection into andtreatment of a damaged spinal disk. The viscosity of a suspending agentcomprising hyaluronic acid can also be more readily adjusted than onecontaining collagen. Such an adjustment can be accomplished by changingthe molecular weight, the concentration, or the amount of cross-linkingof hyaluronic acid in the suspending agent. These properties areseparately adjustable, allowing for improved control of the viscosity ofthe suspending agent in accordance with patient needs. At highconcentrations, hyaluronic acid can have a stiff, viscous quality, likethat of gelatin. At the same time, the shear modulus of hyaluronic acidalso allows for injection using a thin needle. These properties allowfor injection of an implant that provides improved structural integritywithout requiring a larger perforation or increased force. Inrepresentative embodiments, the viscosity of the suspending agent withhyaluronic acid can range from 20,000 to about 350,000 centipoise,advantageously between 50,000 and 200,000 centipoise. Hyaluronic acidmay also be cross-linked to increase the viscosity of a biocompatiblealloplastic implant. The more highly cross-linked the hyaluronic acid,the greater the viscosity. While hyaluronic acid can have a high rate ofelimination and turnover, these properties can be overcome throughmodification and cross-linking. Greater amounts of cross-linking canimpede degradation, increasing the lifespan of a biocompatiblealloplastic implant comprising hyaluronic acid. The concentration ofhyaluronic acid in a suspending agent will also affect lifespan of abiocompatible alloplastic implant, with higher concentrations ofhyaluronic acid leading to longer lifespans. Thus, the elimination andturnover time may be controlled to correspond to the needs of thepatient. In some embodiments, the biocompatible alloplastic implant mayhave a shelf life of at least 12 months when stored between 2° to 8° C.or at room temperature. In certain implementations, the biocompatiblealloplastic implant may have a shelf life of at least 18 months whenstored between 2° to 8° C. or at room temperature.

The viscous properties of hyaluronic acid may also act to preventextrusion from the perforation created during the injection of abiocompatible alloplastic implant. The hydrophilic nature of hyaluronicacid causes it to bind water molecules until completely saturated.Injection of a biocompatible alloplastic implant containing hyaluronicacid that is not completely saturated allows for the suspending agent tobind to more water molecules after placement in the interior of a spinaldisc. When hyaluronic acid binds to water molecules in the interior of adisc, the viscosity and volume of the material inside the disk canincrease, and consequently, prevent extrusion from occurring through theneedle perforation created upon injection.

The annulus fibrosus measures radially between 6 mm to 8 mm. The annulusfibrosus includes a plurality of collagen layers (laminae), rangingbetween 15 to 40 layers. A needle introduced into the nucleus pulposustraverses the collagen layers. The needle may include a stylet such thatintroduction of the needle into the annulus fibrosis causes a majorityof the annular fibers to be compressed rather than cut, which in turnprevents the incidental removal of tissue as a result of the injectionprocess. When the needle is removed following injection, the perforatedtissue may at least partially contract. For example, a 22-gauge needlehas an outer diameter of approximately 700 microns. Upon removal of the22-gauge needle, the perforation in the layers of the annulus fibrosiswill have a diameter of approximately 350 microns or less. When theneedle is removed, the layers of collagen may readjust such that theperforations through at least some of the layers may be offset.Furthermore, the layers of collagen are cross hatched and have adhesiveproperties. For extrusion to occur, an implant would have to traverseeach collagen layers. In response to an axial load, a material having alow viscosity may extrude through each collagen layers, but a highviscosity material, such as a biocompatible alloplastic implantincluding hyaluronic acid may resist extrusion. In some embodiments,such a material may include microspheres having an average diameter ofabout 70 microns.

The concentration of hyaluronic acid in a suspending agent can affectthe saturation level. A higher concentration of hyaluronic acid willrequire more water molecules to become completely saturated. Thus, theconcentration of hyaluronic acid in a suspending agent can be adjustedto change the amount of saturation as desired. In representativeembodiments, the concentration of hyaluronic acid in a suspending agentcan range from 12-50 mg/ml. Concentrations above 20 mg/ml can bind largeamounts of water, and consequently, may be favorable for preventingextrusion from occurring.

In representative embodiments, the average molecular weight ofhyaluronic acid may be at least 1.6 M Da, at least 2.8 M Da., or atleast 3 M Da. In some embodiments, the biocompatible alloplastic implantcan be extruded using an extrusion force between 10 N to 30 N.Hyaluronic acid is a shear thinning polymer. A higher molecular weightof hyaluronic acid also has a greater shear thinning effect. Highermolecular weights of hyaluronic acid also may last longer in the bodyfollowing implantation. Degradation in vivo may be enzymatic or due toapplied forces. This degradation can occur by cleaving of low molecularweight fragments from a polymer chain. Use of higher molecular weighthyaluronic acid will cause larger sections of polymer to remain aftercleaving, improving the amount of time the implant can last in vivo.Furthermore, degradation of a biocompatible alloplastic implant having 3M Da molecular weight hyaluronic acid results in a material that stillhas an appreciable viscosity. In some embodiments, the hyaluronic acidmay have a purity of greater than 95%. The moisture percentage of thehyaluronic acid may be between 8% to 15%. In some embodiments, themoisture percentage of the hyaluronic acid may be less than 20%.

The biocompatible alloplastic implant of the present inventionpreferably comprises a plurality of microparticles, which can comprisesolid microparticles in representative embodiments. The plurality ofmicroparticles can comprise one or more of poly methacrylate,polymethylmethacrylate (PMMA), a cured polymer, a fully polymerizedpolymer, and glass. PMMA microspheres may be linear (uncross-linked) orcross-linked. Cross-linked PMMA may be less brittle than noncross-linked PMMA, and thus more resilient and less prone to fractureunder loads or weight. In modified implementations, the microparticlesmay not be altogether solid, such as implementations involving hollow orporous microparticles. The biocompatible alloplastic implant can in oneimplementation comprise a histocompatible solid in the form of a powder.The microparticles forming the solid may be incorporated into asuspending agent comprising hyaluronic acid. As used herein, the term“microparticles” refers to microparticles (e.g., in a dust or powderform) possessing an average diameter of 500 microns or less. Typically,the average diameter will be greater than about 20 microns rendering themicroparticles too large to be “eaten” by monocytes. The microparticlescan have diameters sufficient to keep them from being washed awaythrough lymph tracts or other tissue tracts from the implantation site.If the microparticles do not have a spherical form, then the diameter asused herein refers to the greatest diameter of the smallest crosssectional area. It is, however, also possible to use smallermicroparticles ranging from 4 to 5 microns or 5 to 10 microns indiameter. In representative embodiments, the microparticles can have anaverage diameter of about 15 to about 300 microns, about 15 to 250microns, about 40 to 300 microns, about 20 to 250 microns, about 80 to180 microns, about 40 microns to 110 microns or about 50 to about 100microns. Use of hyaluronic acid in a suspending agent allows for thelarger average diameters of the microparticles in some implementations,those ranging from about 80 to 300 microns, than would a suspendingagent comprising collagen. In representative configurations, themicroparticles are small enough to be injected through a fine gaugecannula (e.g., 18 gauge) or an injection syringe to the desired spinaldisk region. Particles having the diameters specified herein may have arelatively minimal effect on the surrounding tissues, i.e., the dura ofthe cal sac or nerve root sleeves.

In some embodiments, linear or uncross-linked PMMA microspheres may havea glass transition temperature (Tg) of 105° C. This glass transitiontemperature can cause the the PMMA microspheres to lose sphericity andmechanical properties when in contact with temperatures used forautoclaving (approximately 120° C.). Cross-linked PMMA microspheres havea higher glass transition temperature, which can make a biocompatiblealloplastic implant more stable to thermal and mechanical exposure. Insome embodiments, the PMMA may be cross-linked to an amount sufficientto have a glass transition temperature of 120° C. or greater. In someimplementations, the PMMA may be cross-linked to an amount sufficient tohave a glass transition temperature of 135° C. or greater. In someimplementations, the PMMA may be cross-linked to an amount sufficient tohave a glass transition temperature of 130° C. or greater. Cross-linkedPMMA microspheres may include a cross-linking agent. The cross-linkingagent may include ethylene glycol dimethacrylate which can be less than1% (w/w) of the concentration of the biocompatible alloplastic implant.

Due to the formed surface and size of the microparticles used, they arenot detected by the endogenous macrophages as foreign bodies so that nodefensive reaction takes place. According to a representativeembodiment, the microparticles have spherical forms or spherical-likeforms capable of forming closely-packed arrangements at the site wherethey have been implanted and further capable of being individuallyencapsulated by the scar tissue.

The microparticles can be histocompatible with smooth surfaces free fromcorners and edges, can be dynamically balanced, and can have at leastone of elliptical and spherical forms. For example, the plurality ofmicroparticles typically can comprise a plurality of microspheres, whichcan be inserted into the spinal disk as loose microparticles and remaintherein as loose microparticles.

In representative embodiments of the present invention, thebiocompatible alloplastic implant can comprise 20-60% microspheres. Insome embodiments, the biocompatible alloplastic implant comprising20-60% microspheres can also comprise a suspending agent containinghyaluronic acid with a concentration ranging from 20-50 mg/ml. Combininga concentration of hyaluronic acid within the 20-50mg/ml range with apercentage of microspheres in the 20-60% range can result in abiocompatible alloplastic implant that can be injected through a 22-23gauge needle but will not extrude through the perforation created by theneedle due to increased volume and viscosity after binding to watermolecules in the interior of the spinal disc. In some embodiments, thethe biocompatible alloplastic implant can comprise 25-75% microspheres.

In some embodiments, the biocompatible alloplastic implant can comprisebetween 25% to 50% (w/w) PMMA, 30% to 50% (w/w) PMMA, 38% to 50% (w/w)PMMA, 38% to 48% PMMA, 38% to 44% (w/w) PMMA, 38% to 42% (w/w) PMMA, 43%to 44% (w/w) PMMA, or 40% to 50% (w/w) PMMA. In some embodiments, thePMMA may have a purity of at least 95%.

In representative embodiments of the present invention, the plurality ofmicroparticles can comprise PMMA microspheres. Use of PMMA can create alower adhesive force and coefficient of friction than other polymerstraditionally used in biocompatible implants like silicone. As explainedabove, more highly cross-linked and higher concentration hyaluronic acidsuspending agents are desirable to bind with water on the interior ofthe disc after injection. However, the increased viscosity of suchsuspending agents can require the use of larger needles for injection.The use of PMMA microspheres can reduce the adhesive force andcoefficient of friction present in the biocompatible alloplasticimplant, allowing for injection using a smaller needle, thus creating asmaller perforation for possible extrusion.

It is one aspect of the material and methods described herein that thematerial can be injected into the disk by a physician with a relativelysmall needle, but the material does not extrude from the perforation inthe patient left by the needle after injection. This is accomplishedwith embodiments of the invention without the use of any gelling orsetting agents in the implant material that cause the material topolymerize, gel, or otherwise harden in place after injection throughthe annulus. Therefore an implant of simple composition can be used,reducing the risk of adverse reactions or complications followinginjection.

During a conventional provocative CT diskography, opening spinal-diskpressures are often measured. In the context of diskography, or any ofthe above-mentioned procedures, it is possible in accordance withcertain aspects of the present invention for a spinal-disk openingpressure to be significantly altered by the introduction of thebiocompatible alloplastic implant into the nucleus pulposus of thatspinal disk and, preferably, into a central region of the nucleuspulposus, so that, for example, at least partial sealing of the spinaldisk can be effectuated from the inside out.

As a result of implantation of the biocompatible alloplastic implantinto a spinal disk, a seal or occlusion can be formed in the annulusfibrosis defect via, for example, in one implementation, displacement ofnucleus pulposus from the site of implantation (e.g., an intermediateor, more preferably in some embodiments, central region of the nucleuspulposus) in a direction toward, for example, an annulus fibrosisdefect, so that nucleus pulposus is displaced into a vicinity of theannulus fibrosis defect thus serving to strengthen or otherwise affectat least one property of the spinal disk or defect. In anotherimplementation of the present invention, a seal or occlusion can beformed in the annulus fibrosis defect via, for example, introduction ofthe biocompatible alloplastic implant into the nucleus pulposus in adirect or proximate vicinity of the annulus fibrosis defect thus servingto enhance or otherwise affect at least one property of the spinal diskor defect. For instance, if the biocompatible alloplastic implant isinjected or inserted in either a closed fashion or an open fashion, andif a sufficient portion of the biocompatible alloplastic implant isplaced (and/or caused to solidify or mature) in the center, increasednuclear support can ensue giving rise to not only an increased annularintegrity but also, for example, an increased nuclear stability.

Once placed into the nucleus pulposus, the biocompatible alloplasticimplant may mimic or provide a substitute for at least onecharacteristic of the physiologic structure of the spinal disk. Forexample, the biocompatible alloplastic implant may mimic the spinal diskand operate as a partial artificial disk or operate as a partialartificial nucleus pulposus. Accordingly, a morphology of a disco grammay be improved following implantation of the biocompatible alloplasticimplant. For instance, the accumulation of the microparticles of thebiocompatible alloplastic implant and/or the accumulation of scar tissuearound the microparticles within the nucleus pulposus can impart acertain physical stability to the interior of the spinal disk and/or toexterior portion of the annulus fibrosis. Later testing after thesealant (i.e., the biocompatible alloplastic implant) has matured (e.g.,been incorporated into the host tissue through, for example, formationof permanent scar tissue around the microparticles of the implant) canyield an increase in the pressure gradient of the nucleus pulposus.Also, a slight increase in spinal disk space height may be achieved inproportion to the amount of the biocompatible alloplastic implantinstilled which may vary from spinal disk to spinal disk, but which in arepresentative embodiment does not exceed about 3 to 4 cubic centimeters(ccs) and, typically, is within a range of about 0.5 to 1.5 ccs. Duringinjection, it is advantageous to release pressure on the syringe plungerwhen the tip of the needle is within about 3-5 mm from the outer surfaceof the disk during removal of the needle from the disk.

Regarding maturation of the microparticles, which in a representativeembodiment may comprise PMMA spherical beads, as a result of the sizeand physical stability of the PMMA beads, they cannot be phagocytised orlysed. In order to isolate the foreign body, the animal body can onlyfibrotically wall off the foreign bodies in the form of scar tissue.Such a process takes place with almost any foreign body which cannot bedestroyed by the animal body. Prior to or substantially commensurate intime with installation of the biocompatible alloplastic implant and anyremoval of a part of the spinal disk (if applicable), the annular fibersthat are attached to the vertebra end plates above and below can beminimally resected to allow punctate bleeding to occur from, forexample, the edges of the end plate.

It can be advantageous for the microparticles used according to anembodiment of the present invention to have a smooth surface and be freefrom corners and edges, such that the microparticles don't have sharptransitions on their surfaces. In addition they may not have peaks ofany kind or tapered projections. According to one implementation, thesurface does not have pores. In another implementation, the surfaces maycomprise pores. Although smooth, and especially spherical particles canbe advantageous, in some embodiments, non-smooth microparticles of withcorners or peaks or the like may still be used in the present spinaldisk treatment application.

Fully polymerised PMMA is histocompatible and can be incorporated in thehuman body without harmful toxic or carcinogenic reactions so that itcan be considered as chemically and physically inert and biocompatible.For these reasons, PMMA polymers have already been used formanufacturing implants such as bone cement for the plastic covering ofbone defects in the face and in the cranium, or as in a total hip ortotal knee arthroplasty. The polymer is also being used formanufacturing artificial teeth, as artificial heart valves and formanufacturing intra-ocular lenses and dialysis membranes. In someembodiments, a biocompatible alloplastic implant may include PMMA havingless than 3% MMA monomer, the MMA molecule being non-soluble in water.PMMA having less than 3% MMA monomer is non-toxic and biocompatible. Insome embodiments, endotoxin levels of the biocompatible alloplasticimplant may be less than 0.06 EU/ml. In some embodiments, thebiocompatible alloplastic implant may have a pH value of between 6.5 and7.5. In certain implementations, the biocompatible alloplastic implantmay have a pH value of between 7.0 and 7.5.

The mixing ratio of the components of the suspending agent can be chosenaccording to the needs, and in particular according to the size of thesyringe used for the injection. For example, the viscosity of asuspending agent comprising hyaluronic acid can be controlled byaltering the molecular weight, the concentration, or the amount ofcross-linking of hyaluronic acid in the solution. For the application orinjection of the microparticles used according to an embodiment of thepresent invention, the microparticles can be suspended or slurried in afluid inert medium. In one particular implementation, a ratio of twovolume parts of the suspending agent and one volume part of themicroparticles or polymer microparticles is chosen.

Representative embodiments of a biocompatible alloplastic implant can beprocessed by the following steps: (i) hydrating hyaluronic acid in PBS,(ii) adding PMMA particles, (iii) stirring the composition, (iv) loadingthe implant into a syringe, and (v) sterilizing via autoclave.Autoclaving may be performed at temperatures of about 120° C. Steamautoclave sterilization does not damage PMMA microspheres having a glasstransition temperature above the autoclaving temperature. Thebiocompatible alloplastic implant can be terminally stabilized, meaningthat autoclave sterilization can be performed on whole syringes alreadyfilled with the implant in the barrel, eliminating the need for asepticmaterial processing and loading.

Additionally, medical kits may be produced containing elements necessaryfor treating and/or repairing tendons and ligaments with thetissue-promoting implant. Such a kit may include a quantity of theimplant, and a delivery device, such as a syringe or other applicator.One or more surgical tools used in conventional spinal disk access andrepair surgery may optionally also be advantageously provided in suchkits.

In one preferred embodiment, a biocompatible alloplastic implant mayinclude a suspending agent having sterile PBS and linear, implant grade,endotoxin-free, non-sterile hyaluronic acid having a molecular weight ofgreater than 1.6 M Da, a purity of greater than 95%, a moisturepercentage of between 8% and 15% and a concentration in PBS of between1.0% and 3.0%. The biocompatible alloplastic implant can also includenon-sterile, endotoxin-free, cross-linked PMMA microspheres having aglass transition temperature greater than 130° C., an average diameterbetween 40 and 110 microns, a purity of greater than 95%, aconcentration of PMMA within the biocompatible alloplastic implant ofbetween 25% and 50%, and a conformance within the above lower and upperspecification limits of greater than 80%. The biocompatible alloplasticimplant may be used with a 1 ml long glass pre-fillable syringe having astandard medical grade hypodermic needle, in which the needle is atleast 3 inches in length and 20-guage or smaller. The syringe may have astandard luer female connector for needle connection. The biocompatiblealloplastic implant may have an endotoxin levels of less than 0.06EU/ml, a pH of between 6.5 and 7.5, and a shelf life of greater than 12months when stored between 2° and 8° C. The filled syringe may be steamsterilized and have a sterility assurance level of 10⁻⁶.

In another preferred embodiment, a biocompatible alloplastic implant mayinclude a suspending agent having sterile PBS and linear, implant grade,endotoxin-free, non-sterile hyaluronic acid having a molecular weight ofgreater than 2.8 M Da, a purity of greater than 95%, a moisturepercentage of between 8% and 15% and a concentration in PBS of between1.6% and 2.4%. The biocompatible alloplastic implant can also includenon-sterile, endotoxin-free, cross-linked PMMA microspheres having aglass transition temperature greater than 130° C., an average diameterbetween 50 and 100 microns, a purity of greater than 95%, aconcentration of PMMA within the biocompatible alloplastic implant ofbetween 38% and 48%, and a conformance within the above lower and upperspecification limits of greater than 90%. The biocompatible alloplasticimplant may be used with a 1 ml long glass pre-fillable syringe having astandard medical grade hypodermic needle, in which the needle is atleast 6 inches in length and 21-guage or smaller. The syringe may have astandard luer female connector for needle connection. The biocompatiblealloplastic implant may have an endotoxin levels of less than 0.06EU/ml, a pH of between 670 and 7.5, and a shelf life of greater than 18months when stored between 2° and 8° C. or room temperature. The filledsyringe may be steam sterilized and have a sterility assurance level of10⁻⁶.

Experimental Data

Experiments were performed using a biocompatible alloplastic implantincluding HTL Biosciences sodium hyaluronate (the sodium salt ofhyaluronic acid) and Syringa Lab Supplies Ganzpearl GM-5003 crosslinkedPMMA Poly(methyl methacrylate) microspheres. The sodium hyaluronate hadan intrinsic viscosity of 2.92 m³/kg at 25° C. and an average molecularweight of 3.1 M da. The PMMA microspheres had a diameter range from 53to 106 microns, with a mean diameter of 66.15 microns, a median diameterof 63.51 microns, and a standard deviation of 10.02 microns. Less than1% of the microspheres had diameters outside of the 50-100 micron range.The specific gravity of the PMMA microspheres was 1.19.

Extrusion Force Testing

On Nov. 11, 2015 extrusion force testing was performed for variouscompositions of a biocompatible alloplastic implant having hyaluronicacid and PMMA microspheres with the specifications described above. Whenforming the implant, the sodium hyaluronate was hydrated andreconstituted with sterile PBS. The PMMA beads were washed in 1N NaOH,rinsed in sterile water for injection (SWFI), and dried, but notsterilized. In the experiment, 1 cc BD-Hypak syringes were used toextrude the implant through 22-gauge, 6 inch RELI spinal needles. Priorto testing, the syringes were autoclaved. The syringes underwentterminal sterilization at 120° C. for 15 minutes of exposure under 15-81psi with a slow ramp up and Air-Over-Pressure exhaust. Threeformulations were tested: Formula A having a concentration of hyaluronicacid in PBS of 2.0% and including 40.5% (w/w) PMMA; Formula B having aconcentration of hyaluronic acid in PBS of 2.0% and including 42.5%(w/w) PMMA; and Formula C having a concentration of hyaluronic acid inPBS of 2.2% and including 42.5% (w/w) PMMA. Each formulation was testedat syringe travel rates of 1.5 inches per minute and 2.5 inches perminute, using three different syringes for each travel rate. Theextrusion force testing was performed at room temperature on a Mark-10Force Stand with a calibrated 50 lb load cell. The formulations testedand the mean extrusion forces measured are summarized in Table 1 below.

TABLE 1 MEAN MEAN EXTRUSION EXTRUSION PRODUCT FORCE FORCE CONCENTRATION@ 1.5″/min @ 2.5″/min Formula A: 27.6N 29.0N 2.0% HA base, 40.5% PMMAFormula B: 28.8N 30.8N 2.0% HA base, 42.5% PMMA Formula C:  32.0N** All(3) 2.2% HA base, 42.5% PMMA 1-Syringe Failed syringes failed

Sheep Study

A study was performed by the North American Science Association (NAMSA)using a test article including a composition of 1.2% (w/w) hyaluronicacid, 40.5% (w/w) cross-linked PMMA microspheres, and 58.3% (w/w)buffered PBS. The hyaluronic acid had an average molecular weight of 3.0M Da. The PBS had a pH of 7.1 and an osmolarity of 300 mOs/L. The PMMAmicrospheres had an average diameter of 53 to 106 microns. The glasstransition temperature of the PMMA beads was 135° C., and the specificgravity was 1.19. The PMMA microspheres also contained a linking agent.The rotational viscosity of this formulation was measured at 89,000centipoise with a shear rate of 4 sec⁻¹ and an extrusion force of 29.0 Nusing one technique, and at 190,000 centipoise with a shear rate of 1sec⁻¹ using another technique.

The purpose of the study was to evaluate the local tissue response tothe biocompatible alloplastic implant implanted in the intervertebraldiscs of sheep. The following parameters were measured: cleft formationwith a loss of nucleus pulposus, disintegration of nucleus pulposusmatrix, clones of chondrocyte-like cells, lobulation, extrusion ofnucleus pulposus into vertebral bodies, inflammation,neovascularization, and nerve ingrowth.

The spinal columns of the tested animals were provided to NAMSA withlocation marker designation. Animal 13R had a wire marker located on thetransverse process of the third lumbar vertebrae, per Euthanasia andTissue Collection form. Animal 88Y had a wire marker located on thetransverse process of the third lumbar vertebrae, per Euthanasia andTissue Collection form. Animal 35Y had a wire marker located on thetransverse process of the third lumbar vertebrae, per Euthanasia andTissue Collection form. Animal 13Y had a wire marker located on thetransverse process of the second lumbar vertebrae, per Euthanasia andTissue Collection form. Orientation and disc location was determinedfrom the wire markers for each animal.

The spinal columns for each animal were submerged in 10% neutralbuffered formalin and shipped to NAMSA. After arrival at NAMSA, thelumbar vertebrae were cut along a transverse plane to create functionalspinal units (i.e., caudal half of cranial vertebra, intervertebral discand cranial half of caudal vertebra). The lumbar functional spinal units(FSUs) were fixed in 10% neutral buffered formalin to ensure adequatefixation. Coronal sections of the intervertebral discs were collectedusing a bone saw, decalcified, processed and embedded in paraffinblocks. A minimum of three tissue sections (4-5 μm thick) were preparedof each intervertebral disc to capture the area of the nucleus pulposusand one tissue section of the overlying spinal cord and spinal canal.These sections were stained with hematoxylin and eosin.

Over a three month interval, the intervertebral discs of four animalsfrom Group 1 were evaluated for findings associated with the testarticle and the microscopic appearance of uninjured and injuredintervertebral disc cytoarchitecture which included the nucleus pulposusand anulus fibrosus. The presence, distribution and alterations, such asencapsulation, in the test article were evaluated. The followingfindings in the nucleus pulposus matrix of uninjured and injuredintervertebral discs were evaluated: cleft formation with a loss ofnucleus pulposus, disintegration of nucleus pulposus matrix, clones ofchondrocyte-like cells, lobulation, extrusion of nucleus pulposus intovertebral bodies, inflammation, neovascularization, and nerve ingrowth.

The test article was nonstaining microspheres that were found in theintervertebral disc sections labeled L1-L2 and L3-L4 for all fouranimals (FIG. 1). FIG. 1 shows a test article within the nucleuspolposus of intervertebral disc sections L1-L2 of test animal 13Y. Therewas no tissue reaction (including encapsulation) to the presence of themicrospheres in any of the eight treated intervertebral discs. Themicrospheres were generally in clusters and mainly in the nucleuspulposus, although a few were between bands of the AF (e.g., L1-L2 of13Y). The microspheres were occasionally organized in clusters andsurrounded by a thin layer of basophilic matrix material.

Evidence of injury (i.e., cleft in nucleus pulposus, usually large) wasapparent microscopically in the intervertebral disc sections labeledL2-L3 and L4-L5 for all four animals (FIG. 2), except in several injuredintervertebral discs (L2-L3 of 35Y; L2-L3 of 13R; L1-L2 of 13Y; L3-L4 of13Y and L3-L4 of 88Y). FIG. 2 shoes a cleft in a nucleus pulposus ofintervertebral disc sections L4-L5 of test animal 13R resulting frominjury. The nucleus polposus has degenerative changes that includeclones of chondrocyte-like cells and disintegration of the matrix. Thelack of microscopic evidence of injury may have been the result of theplane of tissue section.

The microscopic findings in the injured intervertebral discs (with orwithout treatment) were present in uninjured intervertebral discs (L5-L6and L6-L7) and were considered nonspecific degenerative findings inintervertebral discs. The microscopic findings included disintegrationof the nucleus pulposus matrix, clefts, lobulation of the nucleuspulposus matrix and the presence of chondrocyte-like cells formingclones.

There was no apparent narrowing of the intervertebral disc space in thehistologic sections. Focal cranial extrusion of the nucleus pulposusinto the adjacent vertebral body was present at L3-L4 of 88Y and caudalextrusion of the nucleus pulposus into the adjacent vertebral body ofL6-L7 intervertebral disc of 88Y. This finding was considered anonspecific degenerative condition. Inflammation, neovascularization andnerve ingrowth were not apparent in the intervertebral disc sections.

After the three month interval, there was no tissue reaction to the testarticle in the intervertebral discs of sheep that were injured by anannular tear. Information regarding the test animals is provided inTable 2 below:

TABLE 2 Test Animal Intervertebral Disc Section Data Animal: L1-L2(Injured, Treated): (1) Large central cleft in the NP, 35Y (2)Lobulation of the NP matrix with multifocal clones of chondrocyte-likecells, (3) Presence of test article in the NP without reaction. L2-L3(Injured, Untreated): (1) Normal NP cytoarchitecture with slightdisintegration of NP matrix, (2) No test article. L3-L4 (Injured,Treated): (1) Central cleft in NP, (2) Lobulation of the NP matrix withmultiple clones of chondrocyte-like cells, (3) Presence of test articlein peripheral NP. L4-L5 (Injured, Untreated): (1) Large central cleft inthe NP, (2) Slight lobulation of the NP matrix with multiple clones ofchondrocyte-like cells, (3) No test article. L5-L6 (Uninjured,Untreated): (1) Normal NP cytoarchitecture with slight disintegration ofNP matrix and a cleft, (2) No test article. L6-L7 (Uninjured,Untreated): (1) Large central cleft in the NP, (2) Lobulation of the NPmatrix with multifocal clones of chondrocyte-like cells, (3)Disintegration of NP matrix, (4) No test article. Animal: L1-L2(Injured, Treated): (1) Large central cleft in the NP, 13R (2)Lobulation of the NP matrix with multifocal clones of chondrocyte-likecells, (3) Presence of test article in the NP without reaction. L2-L3(Injured, Untreated): (1) Normal NP cytoarchitecture with slightdisintegration of NP matrix, (2) No test article. L3-L4 (Injured,Treated): (1) Central cleft in NP, (2) Lobulation of the NP matrix withmultiple clones of chondrocyte-like cells, (3) Presence of test articlein central NP without reaction. L4-L5 (Injured, Untreated): (1) Focalcentral cleft in the NP, (2) Focal lobulation of the NP matrix with afew clones of chondrocyte-like cells, (3) Slight and focaldisintegration of NP matrix (3) No test article. L5-L6 (Uninjured,Untreated): (1) Distortion of NP cytoarchitecture with slightdisintegration of NP matrix and a cleft, (2) No test article. L6-L7(Uninjured, Untreated): (1) Central disintegration of NP matrix, (2)Focal lobulation of the NP matrix with multifocal clones ofchondrocyte-like cells, (3) No test article Animal: L1-L2 (Injured,Treated): (1) Normal NP cytoarchitecture 13Y with slight disintegrationof NP matrix, (2) Presence of test article in NP with slightdisintegration of NP matrix, (3) Presence of test article in AF. L2-L3(Injured, Untreated): (1) Central cleft in NP, (2) Aggregates of NP inAF (3) No test article. L3-L4 (Injured, Treated): (1) Normal NPcytoarchitecture with slight disintegration of NP matrix, (2) Slight andfocal disruption of NP matrix, (3) Test article was present in the AFand a slight amount was present in the NP. L4-L5 (Injured, Untreated):(1) Focal peripheral cleft in the NP, (2) Slight and focaldisintegration of NP matrix (3) No test article. L5-L6 (Uninjured,Untreated): (1) Multifocal disintegration of NP matrix with clefts, (2)Aggregates of NP in AF, (3) Multifocal disruption of AF matrix (4) Notest article. L6-L7 (Uninjured, Untreated): (1) Normal NPcytoarchitecture with slight disintegration of NP matrix, (2) No testarticle. Animal: L1-L2 (Injured, Treated): (1) Large central cleft inthe NP, 88Y (2) Lobulation of the NP matrix with multifocal clones ofchondrocyte-like cells, (3) Slight disintegration of NP matrix, (4)Presence of test article in NP without reaction. L2-L3 (Injured,Untreated): (1) Slight cleft, (2) Slight lobulation, (3) Slight NPmatrix disintegration, (4) No test article. L3-L4 (Injured, Treated):(1) Slight lobulation of the NP matrix, (2) Slight NP matrixdisintegration (3) Focal cranial extrusion of NP into adjacent vertebralbody, (4) A slight amount of test article was present in the NP. L4-L5(Injured, Untreated): (1) Slight cleft formation, (2) Slight lobulationof NP matrix with chondrocyte-like aggregation, (3) Slightdisintegration of NP matrix, (4) No test article. L5-L6 (Uninjured,Untreated): (1) Central cleft in the NP, (2) Lobulation of the NP matrixwith multifocal clones of chondrocyte-like cells, (3) No test article.L6-L7 (Uninjured, Untreated): (1) Central cleft in the NP, (2)Lobulation of the NP matrix with multifocal clones of chondrocyte-likecells, (3) Slight NP matrix disruption, (4) Slight, multifocaldisintegration of AF, (5) Focal caudal extrusion of NP into adjacentvertebral body, (6) No test article.

Representative Methods and Uses

It will be appreciated that the invention has a variety of aspects. Inaccordance with some of these aspects, a biocompatible alloplasticimplant can be utilized for annular welding or sealing of a spinal diskdefect, such as a ruptured spinal disk. The biocompatible alloplasticimplant can be inserted into a ruptured spinal disk, filling a portionof the nucleus pulposus or annulus fibrosis and providing a seal. In oneimplementation, the biocompatible alloplastic implant is inserted into acentral region of the ruptured spinal disk. Insertion of thebiocompatible alloplastic implant into the ruptured spinal disk canattenuate a risk for recurrent spinal disk herniation and restore atleast a portion of a structural integrity or shock absorbing capacity ofthe spinal disk.

In some aspects of the invention, a biocompatible alloplastic implantcontaining hyaluronic acid is inserted into a disk. In certainembodiments, hyaluronic acid acts as a carrier or a suspending agent fora plurality of microparticles previously described herein. Thebiocompatible alloplastic implant containing hyaluronic acid may beinserted with a syringe and needle, via flexible catheters of variablelength and diameter, such as, for example, standard percutaneous needlesand standard catheter tips known in the industry, or with the aid of aninjection syringe, such as a syringe having a 3 or 4″ 18-gauge needle.In representative embodiments, the size of the needle can range from14-gauge to 26-gauge. In some embodiments, the size of the needle canrange from 20-gauge to 24-gauge. In some embodiments, the needlecomprises a pencil point needle.

Hyaluronic acid, acting as a carrier for the microparticles, can beadvantageous in treating tears or fissures on the annulus fibrosus orother defects that form in the spinal disk. Hyaluronic acid can work tocorrect defects both before herniation in order to prevent futurecomplications and after herniation to repair and reinforce the spinaldisk. Additionally, hyaluronic acid can fortify the structural integrityof a spinal disk. Due to the hydrophilic nature of hyaluronic acid, abiocompatible alloplastic implant including microparticles, such as PMMAbeads, and a suspending agent including hyaluronic acid can draw waterinto a spinal disk from the endplates of adjacent vertebrae. Thisattribute of hyaluronic acid can help maintain disk height in a treatedspinal disk. Furthermore, the hydrophilic nature of hyaluronic acid canalso prevent extrusion through the temporary needle perforation in theannulus fibrosis that is created during injection. A biocompatiblealloplastic implant including microparticles and a hyaluronic acidsuspending agent can bind with water molecules after insertion toincrease the viscosity of and volume of the implant within the disc. Theincreased viscosity and volume can prevent extrusion through the needleperforation. Thus, the binding of water molecules with the hyaluronicacid suspending agent can act as an internal curing process to preventextrusion from the disc as well as repairing and reinforcing the disk.Repair and fortification through treatment with a biocompatiblealloplastic implant including a hyaluronic acid suspending agent mayprevent patients from having to undergo repeat surgeries to correct backissues. Treatment can improve stability and flexibility of the spine, aswell the shock absorption properties of the treated spinal disk.

Hyaluronic acid can also be advantageous in treating spinal disks thatare collapsing or weakened. It can fortify those disks and correctdefects. Thus, a biocompatible alloplastic implant including ahyaluronic acid suspending agent may alleviate back pain and preventfurther complications from collapsing or weakened disks.

Embodiments of implants including a hyaluronic acid suspending agent mayalso be beneficial in treating disks adjacent to a planned fusion. Thesedisks may be under a greater risk of developing herniation, tears ordefects. A fusion may also act to worsen any preexisting defects inadjacent spinal disks. A hyaluronic acid suspending agent containingmicroparticles can be used to treat preexisting tears and to fortify thestructural integrity of an adjacent disk before or after a plannedfusion in order to prevent further complications.

A method of treating a spinal disk according to the present inventioncan comprise identifying a defect in a spinal disk and inserting analloplastic bulking agent into the spinal disk to thereby treat thedefect, wherein the alloplastic bulking agent comprises a plurality ofmicroparticles and a suspending agent comprising hyaluronic acid. Theidentifying of a defect can comprise, for example, identifying a defectthrough a scope. In typical implementations, the identifying of a defectcan comprise identifying a focal outpouching comprising a displacementof nucleus pulposus within a partially torn or thinned annulus fibrosisof the spinal disk, can comprise identifying an extrusion comprisingdisplaced nucleus pulposus which remains in continuity with an interiorof the spinal disk through a rent in an annulus fibrosis of the spinaldisk, or can comprise identifying a sequestration comprising displacednucleus pulposus which does not remain in continuity with an interior ofthe spinal disk.

The inserting can comprise inserting an alloplastic bulking agent intothe spinal disk while viewing at least a part of the spinal disk througha scope. The scope can comprise a video fluoroscope, and the insertingcan be fluoroscopically guided. In one implementation, the alloplasticbulking agent can be impregnated with a water soluble radiopaque dye tofacilitate visualization during the inserting of the alloplastic bulkingagent into the spinal disk. The radiopaque dye can comprise barium. In atypical implementation, the inserting can comprise inserting about 3 or4 cubic centimeters (ccs) or less of the alloplastic bulking agent intoa nucleus pulposus of the spinal disk, and in certain implementationsthe inserting comprises inserting about 0.5 to 1.5 cubic centimeters(ccs) of the alloplastic bulking agent into the nucleus pulposus of thespinal disk.

The inserting may be followed by a height of the spinal disk beingincreased, wherein the increase in height is proportional to an amountof the alloplastic bulking agent inserted into the spinal disk. Inaccordance with one aspect of the present invention, the inserting maybe followed by a structural integrity of the spinal disk being improved,compared to a structural integrity of the spinal disk before theinserting. For example, a stability of the annulus fibrosis of thespinal disk may be improved relative to a stability of the annulusfibrosis before the inserting, whereby a biomechanical property of amotion segment of the spinal disk is improved compared to biomechanicalproperty of the motion segment before the inserting.

When the spinal disk is juxtapositioned in proximity to at least one ofan upper vertebra and a lower vertebra, at least one aperture can beformed in an endplate of one or both of the upper vertebra and the lowervertebra. Typically, the spinal disk is juxtapositioned between an uppervertebra and a lower vertebra, and a plurality of apertures are formedin an endplate or endplates of at least one of the upper vertebra andthe lower vertebra. The aperture or apertures can be formed using aneedle, which may already be present in the spinal disk during anongoing procedure such as, for example, a diskography procedure.

In representative implementations of the methods disclosed herein, thedefect comprises a spinal annular defect. For instance, the defect cancomprise an internal disk derangement. Insertion of the alloplasticbulking agent into the spinal disk can cause a seal to be formed in andaround the spinal annular defect. This seal can create a more stablemotion segment of the spinal disk compared to a motion segment of thespinal disk before the inserting, by for example imparting increasedstability to the spinal disk relative to a stability of the spinal diskbefore the inserting.

The inserting can be performed during a diskography procedure, and thedefect can comprise at least one annular rent. During the diskographyprocedure, the identifying can comprise an initial visualization of theat least one rent followed by the inserting being performed during thesame diskography procedure. In accordance with one implementation of theinventive methods disclosed herein, the diskography procedure comprisesa provocative diskography procedure wherein the identifying comprises aninitial visualization of the at least one rent and wherein the insertingis performed during the same provocative diskography procedure.

According to another implementation, the diskography procedure can beperformed percutaneously through one of a posterior, posterolateral,lateral, anterior or anterolateral approach to the spinal disk.

In other implementations, the inserting can be performed during an openprocedure, and can comprise inserting the alloplastic bulking agentusing a syringe and needle into the spinal disk in one of a laminotomy,laminectomy, hemilaminotomy and hemilaminectomy open procedure.

Another method of the present invention that can be performed on aspinal disk includes delivering a bulking material comprising aplurality of microparticles and a suspending agent comprising hyaluronicacid into a spinal disk. The delivering can be preceded by inserting aninjection device into the spinal disk, and the bulking material can bedelivered though the injection device and into the spinal disk. When thespinal disk is positioned in proximity to at least one of an uppervertebra endplate and a lower vertebra endplate, the method can compriseforming one or more apertures or perforations in at least one of theupper vertebra endplate and the lower vertebra endplate.

The delivering of a bulking material can comprise delivering a bulkingmaterial into a nucleus pulposus of the spinal disk, such as a centralor non-perimeter region of the spinal disk. The delivering can bepreceded by detecting a condition in the spinal disk, and the bulkingmaterial can be delivered into the spinal disk to treat the condition.Furthermore, the microparticles can be shaped as, for example,microspheres, and can be uniformly distributed in a suspending agentcomprising hyaluronic acid. Moreover, the detecting of a condition cancomprise detecting a displacement of inner disk material within apartially torn or thinned annulus of the spinal disk, and the deliveringcan comprise delivering an amount on the order of about 3 to 4 cubiccentimeters (ccs) or less of the bulking material into the spinal disk.

The efficacy of the techniques described above may be further improvedby maintaining the patient at a reduced activity level for several weeksfollowing implantation of the biocompatible alloplastic implant. With areduced level of activity, the biocompatible alloplastic implant mayremain in a disc until the annulus can heal in approximately 3-4 weeks.The perforation caused by the injection needle decreases in size overtime due to healing in the mid to outer annulus. Accordingly, thegreatest risk of extrusion occurs during the first 2-3 weeks. Thus, thetechniques described above may include a further step of reducingpatient activity for 2-3 or 3-4 weeks following implantation of thebiocompatible alloplastic implant.

It may also be noted that the techniques described herein can be used toadvantageous effect for treating household pets such as dogs and cats.In these cases, vertebral fusions and similar procedures are often costprohibitive, so any lower cost techniques for disk repair would bebeneficial.

The above-described embodiments have been provided by way of example,and the present invention is not limited to these examples. Multiplevariations and modifications to the disclosed embodiments will occur, tothe extent not mutually exclusive, to those skilled in the art uponconsideration of the foregoing description. Additionally, othercombinations, omissions, substitutions and modifications will beapparent to the skilled artisan in view of the disclosure herein.Accordingly, the present invention is not intended to be limited by thedisclosed embodiments.

What is claimed is:
 1. An implant agent comprising a plurality ofmicroparticles suspended in a non-gelling solution containing hyaluronicacid, for use in repairing and/or improving structural integrity ofspinal disks, wherein the microparticles comprise cross-linkedpolymethymethacrylate (PMMA) microparticles having a glass transitiontemperature of at least 120 degrees C.
 2. The implant agent of claim 1,wherein the solution containing hyaluronic acid comprises cross-linkedhyaluronic acid.
 3. The implant agent of claim 1, wherein the PMMAmicroparticles have an average diameter between 15 microns to 250microns.
 4. The implant agent of claim 1, wherein the concentration ofhyaluronic acid in the solution is between 1.0% and 3.0%.
 5. The implantagent of claim 1, wherein the concentration of hyaluronic acid in thesolution is between 1.6% and 2.4%.
 6. The implant agent of claim 1,wherein the molecular weight of hyaluronic acid in the agent is greaterthan 1.6 M Da.
 7. The implant agent of claim 1, wherein the molecularweight of hyaluronic acid in the agent is greater than 2.8 M Da.
 8. Theimplant agent of claim 1, wherein the concentration of PMMAmicroparticles in the agent is between 25% and 50%.
 9. The implant agentof claim 1, wherein the concentration of PMMA microparticles in theagent is between 38% and 48%.
 10. The implant agent of claim 1, whereinthe solution has a viscosity between 50,000 and 200,000 centipoise. 11.The implant agent of claim 1, wherein the PMMA microparticles have anaverage diameter of between 50 and 100 microns and are present in thesolution at a concentration of between 38 and 48% w/w.
 12. A medical kitcomprising: an agent comprising microparticles suspended in a solutionhaving a viscosity between 50,000 and 200,000 centipoise, wherein themicroparticles comprise cross-linked polymethymethacrylate (PMMA)microparticles having a glass transition temperature of at least 120degrees C.; and a terminally sterilized syringe containing the agent.13. The medical kit of claim 12, wherein the solution containshyaluronic acid, and wherein the concentration of hyaluronic acid in thesolution is between 1.0% and 3.0%.
 14. The medical kit of claim 12,wherein the solution comprises cross linked hyaluronic acid.
 15. Themedical kit of claim 12, wherein the PMMA microparticles have an averagediameter between 15 microns to 250 microns.
 16. The medical kit of claim12, wherein delivery device includes a needle ranging in size frombetween 18-gauge to 25-gauge.
 17. The medical kit of claim 12, whereinthe solution contains hyaluronic acid, and wherein the molecular weightof hyaluronic acid is greater than 1.6 M Da.
 18. The medical kit ofclaim 12, wherein the concentration of PMMA microparticles in the agentis between 25% and 50%.
 19. The medical kit of claim 12, wherein thesyringe has a needle of inner diameter no larger than 900 microns, anouter diameter no larger than 1300 microns, and a length no shorter than3 inches.
 20. The medical kit of claim 12, wherein the syringe has aneedle of inner diameter of between 450 and 240 microns, an outerdiameter of between 750 and 450 microns, and a length of no shorter than5 inches.